The present invention concerns the use of 1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatives for the manufacture of a medicament for treating warm-blooded animals suffering from disease states related to an abnormal enzymatic or catalytic activity of phosphodiesterase IV (PDE IV), and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases. The present invention also relates to new compounds having PDE IV and cytokine inhibiting activity, processes for their preparation and compositions comprising said new compounds.
1-[2-(3,4-diethoxyphenyl)ethyl]-1,2-dihydro-2H-imidazol-2-one and a number of (1,3-dihydro- and 1,3,4,5-tetrahydro-)(1-[2-(3,4-dimethoxyphenyl)propyl]- and 1-[2-(3,4-dimethoxyphenyl)ethyl])-2H-imidazol-2-one derivatives are specifically disclosed in U.S. Pat. No. 3,184,460 as therapeutic agents acting on the central nervous system, in particular, as tranquilizers. Synthetic Communications (1985) 15(10), 883-889, discloses a synthetic pathway for the preparation of 1,3,4,5-tetrahydro-1-[2-(3,4-dimethoxy-phenyl)ethyl]-3-phenylmethyl-2H-imidazol-2-one. In the Chemical and Pharmaceutical Bulletin (1980), 28(6), 1810-1813, 1,3,4,5-tetrahydro-1,3-bis[2-(3,4-dimethoxyphenyl)ethyl]-2H-imidazol-2-one and 1,3,4,5-tetrahydro-1-[2-(3,4-dimethoxyphenyl)ethyl]-2H-imidazol-2-one are disclosed as intermediates in the synthesis of a diazasteroid system. WO 94/12461, WO 94/14742 and WO 94/20446 generically describe a number of 1-(phenylalkyl)-2-hydroxy-imidazole derivatives as selective PDE IV inhibitors.
Unexpectedly, particular 1,3-dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatives show improved PDE IV inhibiting activity over the art compounds. In addition, the compounds of the present invention were found to display cytokine inhibiting activity. In view of these pharmacological properties, the present compounds have therapeutical utility in the treatment of disease states related to an abnormal enzymatic or catalytic activity of PDE IV, or disease related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases.
The present invention concerns the use of compounds of formula (I) for the manufacture of a medicament for treating warm-blooded animals suffering from disease states related to an abnormal enzymatic or catalytic activity of phosphodiesterase IV (PDE IV), and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases, and compounds having the formula 
the N-oxide forms the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein:
R1 and R2 each independently are hydrogen; C1-6alkyl; difluoromethyl; trifluoromethyl; C3-6cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or C1-10alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, C3-7cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen;
R4 is hydrogen, halo or C1-6alkyloxy;
R3 is hydrogen, halo; C1-6alkyl; trifluoromethyl; C3-6cycloalkyl; carboxyl; C1-4alkyloxycarbonyl; C3-6cycloalkylaminocarbonyl; aryl; Het1; or C1-6alkyl substituted with cyano, amino, hydroxy, C1-4alkylcarbonylamino, aryl or Het1; or
R4 is a radical of formula:
xe2x80x94Oxe2x80x94R6 (axe2x88x921); or 
xe2x80x94NHxe2x80x94R7 (axe2x88x922); 
wherein
R6 is hydrogen; C1-6alkyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
R7 is hydrogen; C1-6alkyl; C1-4alkylcarbonyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
R5 is hydrogen, halo, hydroxy or C1-6alkyl; or
R4 and R5 taken together may form a bivalent radical of formula:
xe2x80x94(CH2)nxe2x80x94(bxe2x88x921); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x922); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R8)xe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x923); or 
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94(bxe2x88x924); 
wherein
n is 2, 3, 4 or 5;
R8 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl or p-toluenesulfonyl;
Y is a direct bond, haloC1-4alkanediyl or C1-4alkanediyl;
xe2x80x94Axe2x80x94Bxe2x80x94 is a bivalent radical of formula:
xe2x80x94CR9xe2x95x90CR10xe2x80x94(cxe2x88x921); or 
xe2x80x94CHR9xe2x80x94CHR10xe2x80x94(cxe2x88x922); 
wherein each R9 and R10 independently is hydrogen or C1-4alkyl; and
L is hydrogen; C1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C1-6alkyl substituted with one or two substituents selected from the group consisting of hydroxy, C1-4alkyloxy, C1-4alkyloxycarbonyl, mono- and di(C1-4alkyl)amino, aryl and Het2; C3-6alkenyl; C3-6alkenyl substituted with aryl; piperidinyl; piperidinyl substituted with C1-4alkyl or arylC1-4alkyl; C1-6alkylsulfonyl or arylsulfonyl;
aryl is phenyl or phenyl substituted with one, two or three substituents selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, C3-6cycloalkyl, trifluoromethyl, amino, nitro, carboxyl, C1-4alkyloxycarbonyl and C1-4alkylcarbonylamino;
Het1 is pyridinyl; pyridinyl substituted with C1-4alkyl; furanyl; furanyl substituted with C1-4alkyl; thienyl; thienyl substituted with C1-4alkylcarbonylamino; hydroxypyridinyl, hydroxypyridinyl substituted with C1-4alkyl or C1-4alkoxy-C1-4alkyl; imidazolyl; imidazolyl substituted with C1-4alkyl; thiazolyl; thiazolyl substituted with C1-4alkyl; oxazolyl; oxazolyl substituted with C1-4alkyl; isoquinolinyl; isoquinolinyl substituted with C1-4alkyl; quinolinonyl, quinolinonyl substituted with C1-4alkyl; morpholinyl; piperidinyl; piperidinyl substituted with C1-4alkyl, C1-4alkyloxycarbonyl or arylC1-4alkyl; piperazinyl; piperazinyl substituted with C1-4alkyl, C1-4alkyloxycarbonyl or arylC1-4alkyl; and
Het2 is morpholinyl; piperidinyl; piperidinyl substituted with C1-4alkyl or arylC1-4alkyl; piperazinyl; piperazinyl substituted with C1-4alkyl or arylC1-4alkyl; pyridinyl; pyridinyl substituted with C1-4alkyl; furanyl; furanyl substituted with C1-4alkyl; thienyl or thienyl substituted with C1-4alkyl or C1-4alkylcarbonylamino.
The present invention also relates to a method of treating warm-blooded animals suffering from disease states related to an abnormal enzymatic or catalytic activity of PDE IV, and/or disease states related to a physiologically detrimental excess of cytokines, in particular allergic, atopic and inflammatory diseases, more in particular asthmatic and atopic diseases, most particular atopic dermatitis. Said method comprises the administration of a therapeutically effective amount of a compound of formula (I) or a N-oxide form, a pharmaceutically acceptable acid or base addition salt or a stereochemically isomeric form thereof in admixture with a pharmaceutical carrier.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
In R1 and R2, the saturated 5-, 6- and 7-membered heterocycles containing one or two heteroatoms selected from oxygen, sulfur or nitrogen may suitably be selected from heterocycles such as, for example, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and tetrahydropyranyl. Said heterocyclic radicals are attached to the C1-10alkyl radical by any carbon atom or, where appropriate, by a nitrogen atom.
As used herein the term halo is generic to fluoro, chloro, bromo and iodo; the term C1-4alkyl is meant to include straight chained or branched saturated hydrocarbons having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, 1-methylethyl, 1,1-di-methylethyl, propyl, 2-methylpropyl and butyl; the term C4-6alkyl is meant to include straight chained or branched saturated hydrocarbons having from 4 to 6 carbon atoms such as, for example, 2-methylpropyl, butyl, 2-methylbutyl, pentyl, hexyl and the like; the term C3-6alkyl is meant to include C4-6-alkyl and the lower homologues thereof having 3 carbon atoms such as, for example, propyl and 1-methylethyl; the term C2-6alkyl is meant to include C3-6alkyl and the lower homologues thereof having 2 carbon atoms such as, for example, ethyl; the term C1-6alkyl is meant to include C2-6alkyl and the lower homologue thereof having 1 carbon atom such as, for example, methyl; C1-10alkyl is meant to include C1-6alkyl and the higher homologues thereof having from 7 to 10 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl, 1-methylhexyl, 2-methylheptyl and the like; the term C3-6alkenyl defines straight and branch chained hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; and the carbon atom of said C3-6alkenyl being connected to a nitrogen atom preferably is saturated; the term C3-6cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the term C3-7cycloalkyl is meant to include C3-6cycloalkyl and cycloheptyl; the term C1-2alkanediyl is meant to include methylene, 1,2-ethanediyl and 1,1-ethanediyl; the term C1-3alkanediyl is meant to include C1-2alkanediyl and the higher homologues thereof being straight chained and branched saturated bivalent hydrocarbon radicals having 3 carbon atoms, such as, for example, 1,3-propanediyl, 1,2-propanediyl; the term C1-4alkanediyl is meant to include C1-3-alkanediyl and the higher homologues thereof having 4 carbon atoms such as, for example, 1,4-butanediyl, 2-methyl-1,3-propanediyl and the like.
As used in the foregoing definitions and hereinafter, haloC1-4alkanediyl is defined as mono- or polyhalosubstituted C1-4alkanediyl, in particular C1-4alkanediyl substituted with one or more fluoro atoms.
The pharmaceutically acceptable acid addition salts as mentioned hereinable are meant to comprise the acid addition salt forms which can conveniently be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, hydroxy-acetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicyclic, p-aminosalicyclic, pamoic and the like acids. Conversely, said acid addition salt forms can be converted in three free base forms by treatment with an appropriate base.
The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine lysine and the like.
The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration.
Whenever used hereinafter, the term compounds of formula (I) is meant to include also the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and all stereoisomeric forms.
Some of the compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemical isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diasteromeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically. The pure and mixed stereochemically isomeric forms of the compounds of formula (I) are intended to be embraced with the scope of the present invention.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
The compounds of formula (I) are deemed novel, provided that the compound is other than:
1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)propyl]-2H-imidazol-2-one;
1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)propyl]-5-methyl-2H-imidazol-2-one;
1-[2-(3,4-dimethoxyphenyl)ethyl]-1,3,4,5-tetrahydro-2H-imidazol-2-one;
1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)ethyl]-2H-imidazol-2-one;
1-[2-(3,4-dimethoxyphenyl)propyl]-1,3,4,5-tetrahydro-2H-imidazol-2-one;
1-[2-(3,4-diethoxyphenyl)ethyl]-1,3-dihydro-2H-imidazol-2-one;
1,3-bis[2-(3,4-dimethoxyphenyl)ethyl]-1,3,4,5-tetrahydro-2H-imidazol-2-one; or
1-[2-(3,4-dimethoxyphenyl)ethyl]-3-phenylmethyl-1,3,4,5-tetrahydro-2H-imidazol-2-one.
Thus, the invention concerns novel compounds having the formula 
the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein:
R1 and R2 each independently are hydrogen; C1-6alkyl; difluoromethyl; trifluoromethyl; C3-6cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or C1-10alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, C3-7cycloalkyl and a saturated 5-, 6- 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen;
R3 is hydrogen, halo or C1-6alkyloxy;
R4 is hydrogen, halo; C1-6alkyl; trifluoromethyl; C3-6cycloalkyl; carboxyl; C1-4alkyloxycarbonyl; C3-6cycloalkylaminocarbonyl; aryl; Het1; or C1-6alkyl substituted with cyano, amino, hydroxy, C1-4alkylcarbonylamino, aryl or Het1; or
R4 is radical of formula:
xe2x80x94Oxe2x80x94R6 (axe2x88x921); or 
xe2x80x94NHxe2x80x94R7 (axe2x88x922); 
wherein
R6 is hydrogen; C1-6alkyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
R7 is hydrogen; C1-6alkyl; C1-4alkylcarbonyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
R5 is hydrogen, halo, hydroxy or C1-6alkyl; or
R4 and R5 taken together may form a bivalent radical of formula:
xe2x80x94(CH2)nxe2x80x94(bxe2x88x921); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x922); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R8)xe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x923); or 
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94(bxe2x88x924); 
wherein
n is 2, 3, 4 or 5;
R8 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl or p-toluenesulfonyl;
Y is a direct bond, haloC1-4alkanediyl or C1-4alkanediyl;
xe2x80x94Axe2x80x94Bxe2x80x94 is a bivalent radical of formula:
xe2x80x94CR9xe2x95x90CR10xe2x80x94(cxe2x88x921); or 
xe2x80x94CHR9xe2x80x94CHR10xe2x80x94(cxe2x88x922); 
wherein each R9 and R10 independently is hydrogen or C1-4alkyl; and
L is hydrogen; C1-6alkyl; C1-6alkylcarbonyl; C1-6alkyloxycarbonyl; C1-6alkyl substituted with one or two substituents selected from the group consisting of hydroxy, C1-4alkyloxy, C1-4alkyloxycarbonyl, mono- and di(C1-4alkyl)amino, aryl and Het2; C3-6alkenyl; C3-6alkenyl substituted with aryl; piperidinyl; piperidinyl substituted with C1-4alkyl or arylC1-4alkyl; C1-6alkylsulfonyl or arylsulfonyl;
aryl is phenyl or phenyl substituted with one, two or three substituents selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, C3-6cycloalkyl, trifluoromethyl, amino, nitro, carboxyl, C1-4alkyloxycarbonyl and C1-4alkylcarbonylamino;
Het1 is pyridinyl; pyridinyl substituted with C1-4alkyl; furanyl; furanyl substituted with C1-4alkyl; thienyl; thienyl substituted with C1-4alkylcarbonylamino; hydroxy-pyridinyl, hydroxypyridinyl substituted with C1-4alkyl or C1-4alkoxyC1-4alkyl; imidazolyl; imidazolyl substituted with C1-4alkyl; thiazolyl; thiazolyl substituted with C1-4alkyl; oxazolyl; oxazolyl substituted with C1-4alkyl; isoquinolinyl; isoquinolinyl substituted with C1-4alkyl; quinolinonyl, quinolinonyl substituted with C1-4alkyl; morpholinyl; piperidinyl; piperidinyl substituted with C1-4alkyl, C1-4alkyloxycarbonyl or arylC1-4alkyl; piperazinyl; piperazinyl substituted with C1-4alkyl, C1-4alkyloxycarbonyl or arylC1-4-alkyl; and
Het2 is morpholinyl; piperidinyl; piperidinyl substituted with C1-4alkyl or arylC1-4alkyl; piperazinyl; piperazinyl substituted with C1-4alkyl or aryl C1-4alkyl; pyridinyl; pyridinyl substituted with C1-4alkyl; furanyl; furanyl substituted with C1-4alkyl; thienyl or thienyl substituted with C1-4alkyl or C1-4alkylcarbonylamino:
provided that the compound is not:
1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)propyl]-2H-imidazol-2-one;
1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)propyl]-5-methyl-2H-imidazol-2-one;
1-[2-(3,4-dimethoxyphenyl)ethyl]-1,3,4,5-tetrahydro-2H-imidazol-2-one;
1,3-dihydro-1-[2-(3,4-dimethoxyphenyl)ethyl]-2H-imidazol-2-one;
1-[2-(3,4-dimethoxyphenyl)propyl]-1,3,4,5-tetrahydro-2H-imidazol-2-one;
1-[2-(3,4-dimethoxyphenyl)ethyl]-1,3-dihydro-2H-imidazol-2-one;
1,3-bis[2-(3,4-dimethoxyphenyl)ethyl]-1,3,4,5-tetrahydro-2H-imidazol-2-one; or
1-[2-(3,4-dimethoxyphenyl)ethyl]-3-phenylmethyl-1,3,4,5-tetrahydro-2H-imidazol-2-one.
The subgroups as defined hereinafter are described as subgroups of the compounds of formula (I) and are meant to be also subgroups of the compounds of formula (Ixe2x80x2).
A first set of particular groups of compounds of formula (I) or of compounds of formula (Ixe2x80x2) consists of those wherein one or more of the following provisions apply:
a) R1 is hydrogen; C1-6alkyl; difluoromethyl; C3-6cycloalkyl; tetrahydrofuranyl; bicyclo[2.2.1]-2-heptenyl; arylsulfonyl; or C1-10alkyl substituted with C3-7cycloalkyl or tetrahydrofuranyl; and R2 is C1-6alkyl, difluoromethyl or trifluoromethyl;
b) R3 is hydrogen;
c) R4 is hydrogen, C1-6alkyl, C3-6-cycloalkyl, hydroxy, C1-6alkyloxy, trifluoromethyl, halo, amino, cyanoC1-6-alkyl, C1-6alkylcarbonylamino, aryl, arylC1-6alkyl, Het1C1-6alkyl and R5 is hydrogen, C1-6alkyl or hydroxy, preferably R4 and R5 each independently are hydrogen or C1-6alkyl;
d) R4 and R5 are taken together to form a radical of formula (bxe2x88x921) or (bxe2x88x922), preferably a radical of formula (bxe2x88x921) wherein n is 2;
e) Y is a direct bond, methylene or 1,2-ethanediyl, preferably Y is methylene;
f) L is hydrogen, C1-6alkyl, optionally substituted C3-6alkenyl, C1-6alkyloxycarbonyl, C1-6alkyloxycarbonylC1-6alkyl or arylC1-6alkyl, preferably L is hydrogen;
g) xe2x80x94Axe2x80x94Bxe2x80x94 is a bivalent radical of formula (cxe2x88x921) or (cxe2x88x922), preferably a bivalent radical of formula (cxe2x88x921) wherein R9 and R10 are both hydrogen.
An interesting subgroup within said first set of groups consists of those compounds of formula (I) or of compounds of formula (Ixe2x80x2) wherein R1 is C1-6alkyl, C3-6cycloalkyl or C1-10alkyl substituted with C3-7cycloalkyl and R2 is C1-6alkyl.
Another interesting subgroup within said first set of groups consists of those compounds of formula (I) or of compounds of formula (Ixe2x80x2) wherein Y is methylene.
A second set of particular groups of compounds of formula (I) or of compounds of formula (Ixe2x80x2) consists of those wherein one or more of the following provisions apply:
1) R1 is hydrogen; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; bicyclo[2.2.1]-2-heptenyl; C1-6alkylsulfonyl; arylsulfonyl; or C1-10alkyl substituted with one or two substituents each independently selected from pyridinyl, thienyl, furanyl, C3-7cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen;
2) R2 is hydrogen, C3-6cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or C1-10alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, C3-7cycloalkyl and a saturated 5-, 6- and 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen;
3) R3 is halo or C1-6alkyloxy;
4) R4 halo; trifluoromethyl; C3-6cycloalkyl; C3-6cycloalkylaminocarbonyl; aryl; Het1; or C1-6alkyl substituted with cyano, amino, hydroxy, C1-4alkylcarbonylamino, aryl or Het1; or
R4 is a radical of formula:
xe2x80x94Oxe2x80x94R6 (axe2x88x921); or 
xe2x80x94NHxe2x80x94R7 (axe2x88x922); 
wherein
R6 is C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxy-carbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
R7 is hydrogen; C1-6alkyl; C1-4alkylcarbonyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
5) R5 is halo;
6) R5 is hydroxy and R4 is other than hydrogen or C1-6alkyl;
7) R4 and R5 taken together form a bivalent radical of formula:
xe2x80x94(CH2)nxe2x80x94(bxe2x88x921); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x922); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R8)xe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x923); or 
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94(bxe2x88x924); 
wherein
n is 2, 3, 4 or 5;
R8 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl or p-toluenesulfonyl;
8) xe2x80x94Axe2x80x94Bxe2x80x94 is a bivalent radical of formula (cxe2x88x922);
9) L is C1-6alkyl substituted with hydroxy or C1-4alkyloxy; C3-6alkenyl; C3-6alkenyl substituted with aryl; C1-6alkylsulfonyl or arylsulfonyl.
An interesting subgroup within said second set of groups consists of those compounds of formula (I) or of compounds of formula (Ixe2x80x2) wherein
R4 is halo; trifluoromethyl; C3-6cycloalkyl; C3-6cycloalkylaminocarbonyl; aryl; Het1; or C1-6alkyl substituted with cyano, amino, hydroxy, C1-4alkylcarbonylamino, aryl or Het1; or
R4 is radical of formula:
xe2x80x94Oxe2x80x94R6 (axe2x88x921); or 
xe2x80x94NHxe2x80x94R7 (axe2x88x922); 
wherein
R6 is C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
R7 hydrogen; C1-6alkyl; C1-4alkylcarabonyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl; or
R5 is halo; or
R4 and R5 taken together form a bivalent radical of formula:
xe2x80x94(CH2)nxe2x80x94(bxe2x88x921); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x922); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R8)xe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x923); or 
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94(bxe2x88x924); 
R8 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl or p-toluenesulfonyl.
Another interesting subgroup within said second set of groups consists of those compounds of formula (I) or of compounds of formula (Ixe2x80x2) wherein R1 is hydrogen; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected form oxygen, sulfur or nitrogen; bicyclo[2.2.1]-2-heptenyl; C1-6alkylsulfonyl; arylsulfonyl; or C1-10alkyl substituted with one or two substituents each independently selected from pyridinyl, thienyl, furanyl, C3-7cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen.
A third set of particular groups of compounds of formula (I) or of compounds of formula (Ixe2x80x2) consists of those wherein one or more of the following provisions apply:
1) R1 is hydrogen; C1-6alkyl; difluoromethyl; trifluoromethyl; a saturated 5- , 6- or 7- membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or C1-10alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, C3-7cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen;
2) R2 is hydrogen; C3-6cycloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or C1-10alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, C3-7cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen;
3) R4 is halo; C3-6cycloalkyl; C3-6cycloalkylaminocarbonyl; aryl; Het1; or C1-6alkyl substituted with amino, C1-4alkylcarbonylamino, aryl or Het1; or substituted with amino, C1-4alkylcarbonylamino, aryl or Het1; or
R4 is a radical of formula:
xe2x80x94Oxe2x80x94R6 (a-1); or 
xe2x80x94NHxe2x80x94R7 (a-2); 
wherein
R6 is C1-6alkyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
R7 is hydrogen; C1-6alkyl; C1-4alkylcarbonyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
4) R5 is halo;
5) R4 and R5 taken together form a bivalent radical of formula:
xe2x80x94(CH2)nxe2x80x94(bxe2x88x921); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x922); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R8)xe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x923); or 
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94(bxe2x88x924); 
wherein
n is 2, 3, 4 or 5;
R8 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl or p-toluenesulfonyl;
6) xe2x80x94Axe2x80x94Bxe2x80x94 is a bivalent radical formula (c-2).
An interesting subgroup within said third set of groups consists of those compounds of formula (I) or of compounds of formula (Ixe2x80x2) wherein R4 is halo; C3-6cycloalkyl; C3-6cycloalkylaminocarbonyl; aryl; Het1; or C1-6alkyl substituted with amino, C1-4alkylcarbonylamino, aryl or Het1; or R4 is a radical of formula:
xe2x80x94Oxe2x80x94R6 (a-1); or 
xe2x80x94NHxe2x80x94R7 (a-2); 
wherein
R6 is C1-6alkyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyl-oxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
R7 is hydrogen; C1-6alkyl; C1-4alkylcarbonyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl; or
R5 is halo; or
R4 and R5 taken together form a bivalent radical of formula:
xe2x80x94(CH2)nxe2x80x94(bxe2x88x921); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x922); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R8)xe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x923); or 
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94(bxe2x88x924); 
wherein
n is 2, 3, 4 or 5;
R8 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl or xcfx81-toluenesulfonyl;
Another interesting subgroup within said third set of groups consists of those compounds of formula (I) or of compounds of formula (Ixe2x80x2) wherein R1 is hydrogen; C1-6alkyl; difluoromethyl; trifluoromethyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; Cl1-6alkylsulfonyl; arylsulfonyl; or C1-10alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, C3-7cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen.
A fourth set of particular groups of compounds of formula (I) or of compounds of formula (Ixe2x80x2) consists of those wherein one or more of the following provisions apply:
1) R1 is hydrogen; a saturated 5- 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or C1-10alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, C3-7cycloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen;
2) R2 is hydrogen; C3-6cyloalkyl; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]heptanyl; C1-6alkylsulfonyl; arylsulfonyl; or C1-10alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, C3-7cycloalkyl and a saturated 5- 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen;
3) R4 is C1-6alkyl; trifluoromethyl; C3-6cycloalkyl; carboxyl; C1-4alkyloxycarbonyl; C3-6cycloalkylaminocarbonyl; or C1-6alkyl substituted with cyano, amino, hydroxy, C1-4alkylcarbonylamino; or
R4 is a radical of formula:
xe2x80x94Oxe2x80x94R6 (a-1); or 
xe2x80x94NHxe2x80x94R7 (a-2); 
wherein
R6 is C1-6alkyl substituted with carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
R7 is hydrogen; C1-6alkyl; C1-4alkylcarbonyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
4) R5 is C1-6alkyl;
5) R4 and R5 taken together form a bivalent radical of formula:
xe2x80x94(CH2)nxe2x80x94(bxe2x88x921); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x922); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R8)xe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x923); or 
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94(bxe2x88x924); 
wherein
n is 2, 3, 4 or 5;
R8 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl or p-toluenesulfonyl;
6) xe2x80x94Axe2x80x94Bxe2x80x94 is a bivalent radical of formula (c-2).
An interesting subgroup within said fourth set of groups consists of those compounds of formula (I) or of compounds or formula (Ixe2x80x2) wherein
R4 is C1-6alkyl; trifluoromethyl; C3-6cyloalkyl; carboxyl; C1-4alkyloxycarbonyl; C3-6cycloalkylaminocarbonyl; or C1-6alkyl substituted with cyano, amino, hydroxy, C1-4alkylcarbonylamino; or
R4 is a radical of formula:
xe2x80x94Oxe2x80x94R6 (a-1); or 
xe2x80x94NHxe2x80x94R7 (a-2); 
wherein
R6 is C1-6alkyl substituted with carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl;
R7 is hydrogen; C1-6alkyl; C1-4alkylcarbonyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4alkyl)amino, Het1 or aryl; or
R5 is C1-6alkyl; or
R4 and R5 taken together form a bivalent radical of formula:
xe2x80x94(CH2)nxe2x80x94(bxe2x88x921); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x922); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R8)xe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x923); or 
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94(bxe2x88x924); 
wherein
n is 2, 3, 4 or 5;
R8 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl or p-toluenesulfonyl.
Another interesting subgroup within said fourth set of groups consists of those compounds of formula (I) or of compounds of formula (Ixe2x80x2) wherein R1 hydrogen; a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; indanyl; bicyclo[2.2.1]-2-heptenyl; bicyclo[2.2.1]-heptenyl; C1-6alkylsulfonyl; arylsulfonyl; or C1-10alkyl substituted with one or two substituents each independently selected from aryl, pyridinyl, thienyl, furanyl, C3-7cycloalkyl and a saturated 5- 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen.
Preferred compounds are those compounds of formula (I) or of compounds of formula (Ixe2x80x2) wherein R4 is C3-6cycloalkyl; C3-6cycloalkylaminocarbonyl; or C1-6alkyl substituted with amino or C1-4alkylcarbonylamino; or
R4 is a radical of formula:
xe2x80x94Oxe2x80x94R6 (a-1); or 
xe2x80x94NHxe2x80x94R7 (a-2); 
wherein
R6 is C1-6alkyl substituted with carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(C1-4 alkyl)amino, Het1 or aryl;
R7 is hydrogen; C1-6alkyl; C1-4alkylcarbonyl; C1-6alkyl substituted with hydroxy, carboxyl, C1-4alkyloxycarbonyl, amino, mono- or di(CC1-4alkyl)amino, Het1 or aryl; or
R4 and R5 taken together form a bivalent radical of formula:
xe2x80x94(CH2)nxe2x80x94(bxe2x88x921); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x922); 
xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R8)xe2x80x94CH2xe2x80x94CH2xe2x80x94(bxe2x88x923); or 
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94(bxe2x88x924); 
wherein
n is 2, 3, 4 or 5;
R8 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl or p-toluenesulfonyl.
Also preferred compounds are those compounds of formula (I) or of compounds of formula (Ixe2x80x2) wherein R1 is hydrogen; a saturate 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen; bicyclo[2.2.1]-2-heptenyl; C1-6alkylsulfonyl; arylsulfonyl; or C1-10alkyl substituted with one or two substituents each independently selected from pyridinyl, thienyl, furanyl, C3-7cyloalkyl and a saturated 5-, 6- or 7-membered heterocycle containing one or two heteroatoms selected from oxygen, sulfur or nitrogen.
More preferred compounds are those compounds of formula (I) or of compounds of formula (Ixe2x80x2) wherein R1 is C3-6cycloalkyl or methyl substituted with C3-7cycloalkyl, R2 is C1-6alkyl, R3 is hydrogen, R4 is C1-6alkyl, R5 is hydrogen or C1-6alkyl, or R4 and R5 are taken together to form a radical of formula (b-1) wherein n is 2, Y, xe2x80x94Axe2x80x94Bxe2x80x94 is a bivalent radical of formula (c-1) wherein R9 and R10 are both hydrogen, Y is methylene and L is hydrogen.
Most preferred compounds are selected from:
1-[[1-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclopropyl]methyl]-1,3-dihydro-2H-imidazol-2-one; 1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-methylpropyl]-1,3-di hydro-2H-imidazol-2-one; 1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]-1,3- dihydro-2H-imidazol-2-one; and 1-[2-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-propyl]-1,3-dihydro-2H-imidazol-2-one; the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof.
Whenever used hereinafter, R1 to R10, xe2x80x94Axe2x80x94Bxe2x80x94 and L are defined as under formula (I) unless otherwise indicated.
The compounds of formula (I) can generally be prepared by N-alkylating a 1,3-dihydro-2H-imidazol-2-one derivative of formula (II) with an appropriately substituted alkylating agent of formula (III), wherein W1 is a reactive leaving group such as, for example, a halogen. 
Said N-alkylation may conveniently be performed in the presence of a base such as, for example, sodium hydride, butyllithium or sodium bis(trimethylsilyl)amide, in a reaction-inert solvent such as, for example, tetrahydrofuran, optionally cooled on the ice-bath. The reaction is preferably performed under a reaction inert atmosphere such as, for example, oxygen free nitrogen. It may be advantageous to add to the reaction mixture a crown ether, e.g., 1,4,7,10,13,16-hexaoxacyclooctadecane and the like or a complexing agent such as for example, tris[2-(2-methoxyethoxy)]ethanamine and the like. Stirring may enhance the rate of the reaction. In case intermediates of formula (II), wherein L is replaced by a suitable protecting group, are used in said N-alkylation reaction, compounds of formula (I) wherein L is hydrogen, said compounds being represented by compounds of formula (I-a), may be obtained using art-known deprotection reactions.
In this and following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography.
Alternatively, compounds of formula (I) may be prepared by reacting an organometallic intermediate of formula (IV), wherein M is an appropriate metal ion or metalcomplex ion such as, for example, Li+, (MgBr)+, B(OH)2+or Sn(CH3)3+, with a suitable 1,3-dihydro-2H-imidazol-2-one derivative of formula (V) wherein W2 is a reactive leaving group such as, for example, a halogen. In case R4 and R5 are taken together and form a radical of formula (b-1), (b-2), (b-3) or (b-4), W2 may also be a cyanide moiety provided that the intermediate of formula (IV) is a Grignard reagent. 
Said reaction may be performed in a reaction-inert solvent such as, for example, dimethoxyethane, tetrahydrofuran or diethylether. Stirring and heating may enhance the rate of the reaction. In case intermediates of formula (V), wherein L is replaced by a suitable protecting group, are used in said reaction, compounds of formula (I) wherein L is hydrogen, said compounds being represented by compounds of formula (I-a), may be obtained using art-known deprotection reactions.
Compounds of formula (I-a) wherein xe2x80x94Axe2x80x94Bxe2x80x94 is a radical of formula (c-1), said compounds being represented by formula (I-a-1), can conveniently be prepared by cyclization of an intermediate of formula (VI) or a functional derivative thereof in the presence of a suitable acid such as, for example, hydrochloric acid. 
Said cyclization may be performed in a reaction inert solvent such as, for example, water, methanol or a mixture thereof. Stirring and heating may enhance the rate of the reaction.
In particular, compounds of formula (I-a-1) wherein R5 is hydroxy and Y is methylene, said compounds being represented by formula (I-a-1-1), may be prepared by cyclization of an intermediate of formula (VI-I) wherein P is hydrogen or, preferably, is a trimethylsilyl protecting group or a functional derivative thereof, in a manner analogous to the one described for the preparation of a compound of formula (I-a-1) from an intermediate of formula (VI). 
Compounds of formula (I-a-1) may also be prepared by cyclization of an intermediate of formula (VII) or a functional derivative thereof in the presence of a suitable isocyanate, such as, for example, potassium isocyanate or trimethylsilyl isocyanate. 
Alternatively, compounds of formula (I-a-1) may also be prepared by reacting an intermediate of formula (VII) with a suitable cyanide such as, for example, potassium cyanide, thus obtaining the corresponding N-Cyanide derivative which may be further hydrolyzed in the presence of an acid such as, for example, hydrochloric acid, keeping the pH of the reaction mixture basic. The thus formed corresponding ureum derivative is then further cyclized in the presence of an excess of an acid such as, for example, hydrochloric acid, to a compound of formula (I-a-1). 
Compounds of formula (I-a) wherein xe2x80x94Axe2x80x94Bxe2x80x94 is a radical of formula (c-2), said compounds being represented by formula (I-a-2), can be obtained by cyclization of an intermediate of formula (VIII) or a functional derivative thereof in the presence of a suitable reagent such as, for example, phosgene, ureum or N,Nxe2x80x2-carbonyldiimidazole. 
The compounds of formula (I) can also be converted into each other following art-known procedures of functional group transformation.
For example, compounds of formula (I) wherein L is other than hydrogen, said compounds being represented by formula (I-b), may be prepared by reacting a compound of formula (I-a) with Lxe2x80x3-W3 (IX), wherein Lxe2x80x3 is the same as L defined under formula (I) but other than hydrogen and W3 is a reactive leaving group such as, for example, a halogen atom. 
Also, art-known addition reactions may be used to convert compounds of formula (I-a) into compounds of formula (I-b).
Compounds of formula (I-b) wherein xe2x80x94Axe2x80x94Bxe2x80x94 is a radical of formula (c-2), said compounds being represented by formula (I-b-2), can be prepared by hydrogenation of compounds of formula (I-b) wherein xe2x80x94Axe2x80x94Bxe2x80x94 is a radical of formula (c-1), said compounds being represented by formula (I-b-1), using art-known hydrogenation techniques. For instance, hydrogen in the presence of a suitable catalyst such as, for example, palladium or platinum supported on for instance charcoal may be used as an appropriate hydrogenation agent.
Compounds of formula (I-a-1) can be prepared by dehydrogenation of compounds of formula (I-a-2) using art-known dehydrogenation techniques. For instance, refluxing a compound of formula (I-a-2) in a reaction-inert solvent such as, for example, xcfx81-xylene, in the presence of a suitable catalyst such as, for example, palladium or platinum supported on for instance charcoal may be used as a dehydrogenation technique.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Intermediates mentioned hereinabove may be prepared following art-known techniques.
In particular, intermediates of formula (VI) may be prepared by first N-acylating an amine of formula (X) with phenyl chloroformate or a functional derivative thereof. Said N-acylation can conveniently be performed in a reaction inert solvent such as, for example, dichloromethane, benzene or toluene, optionally cooled on an ice-bath, and in the presence of a base such as, for example, N,N-diethylethanamine or sodium-bicarbonate. The thus obtained intermediate may be subsequently reacted with 2,2-(di-C1-4alkyloxy)ethanamine or a functional derivative thereof, to form an intermediate of formula (VI). Said reaction can conveniently be performed in a reaction inert solvent such as, for example, 1,4-dioxane, in the presence of a catalyst such as, for example, N,N-diethyl ethanamine, and optionally in the prescence of a catalyst such as, for example, N,N-dimethyl-pyridinamine. Stirring and elevated temperatures may enhance the rate of the reaction. 
Also, intermediates of formula (VI) may be directly formed by reacting an intermediate of formula (X) with a suitable reagent such as, for example, 2,2-(diC1-4alkyloxy)-ethanisocyanate, phenyl [2,2-di(C1-6alkyloxy)]ethyl)carbamate or a functional derivative of any one of said reagents. 
In particular, intermediates of formula (VI-1) may be prepared by reacting an intermediate of formula (X) wherein R5 is a hydroxy group or, preferably, a protected hydroxy group, the protective group P being a trimethylsilyl protecting group or a functional derivative thereof, and Y is methylene, said intermediates being represented by formula (X-1), with N-[2,2-di(C1-4alkyl)ethyl]-1H-imidazole-1-carboxamide or a functional derivative thereof. 
Intermediates of formula (VII) can be prepared by reacting an amine of formula (X) with an intermediate of formula (XI) wherein W4 is a reactive leaving group such as, for example, a halogen. 
Alternatively, intermediates of formula (VII) may be prepared by reacting an intermediate of formula (III) with 2,2-(diC1-4alkyloxy)ethanamine or a functional derivative thereof. 
Some of the intermediates of formula (X) are described in WO 92/00968, WO 93/15044 and WO 93/15045.
In particular, intermediates of formula (X) may be prepared by reacting an intermediate of formula (III) with an intermediate of formula (XII) wherein M is an appropriate metal ion or metalcomplex ion such as, for example, Li+or (MgBr)+, and P is a suitable protecting group such as, for example, (1,1-dimethylethyl)oxycarbonyl. The thus obtained protected intermediates of formula (X) may subsequently be deprotected by art-known techniques such as, for example, acid hydrolysis. 
Intermediates of formula (X) wherein Y is a direct bond or C1-3 alkanediyl, said Y being represented by Yxe2x80x2, and said intermediates being represented by formula (Xxe2x80x2), may be prepared by reducing the unsaturated carbon-nitrogen bond in the intermediates of formula (XIII) with a suitable reducing agent such as, for example, lithium aluminum hydride or hydrogen in the presence of a catalyst such as, for example, Raney nickel. The cyanide moiety in the intermediates of formula (XIII) may also be replaced by a functional derivative thereof such as, for example, an oxime moiety. 
Some of the intermediates of formula (XIII) are described in WO 92/00968, WO 93/15044 and WO 93/15045.
In particular, intermediates of formula (XIII) wherein R4 and R5 are taken together to form a radical of formula (b-1) and Yxe2x80x2 is a direct bond, said intermediates being represented by formula (XIII-b), may be prepared by reacting an intermediate of formula (XIII) wherein xe2x80x94C(R4R5)xe2x80x94Yxe2x80x2xe2x80x94 is xe2x80x94CH2xe2x80x94, said intermediates being represented by formula (XIII-a), with W6xe2x80x94(CH2)nxe2x80x94W6 (XV) wherein W6 is a reactive leaving group such as, for example, a halogen, and n is 2, 3, 4 or 5. 
Said reaction may conveniently be performed in a reaction inert solvent such as, for example, water, tetrahydrofuran or dimethylsulfoxide, and in the presence of benzyltriethytammonium chloride and a base such as, for example, sodium hydroxide. Stirring and elevated temperatures may enhance the rate of the reaction.
Intermediates of formula (X) wherein Y is methylene and R5 is hydrogen, said intermediates being represented by formula (X-a), may be prepared by reducing a nitro derivative of formula (XIV) with a suitable reducing agent such as, for example, lithium aluminium hydride. 
Intermediates of formula (X-1) may be prepared by reacting an intermediate of formula (XVI), wherein R4 is restricted to those moieties that do not interfere with the reaction such as, for example, hydrogen, optionally substituted C1-6 alkyl, C3-6 cycloalkyl, aryl and Het1, with trimethylsilyl cyanide or a functional derivative thereof in the presence of a suitable catalyst such as, for example, zinc iodide, and in a reaction-inert solvent such as, for example, dichloromethane; thus forming an intermediate of formula (XIII) wherein Yxe2x80x2 is a direct bond and R5 is hydroxy or, preferably, a protected hydroxy group, the protective group P being a trimethylsilyl protecting group or a functional derivative thereof, said intermediates being represented by formula (XIII-c). Subsequently, the nitrile derivative of formula (XIII-c) may be reduced to the corresponding amine of formula (X-1) using art-known techniques such as, for example, reduction with hydrogen in the presence of a suitable catalyst such as, for example, Raney nickel. 
The compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, are potent inhibitors of the phosphodiesterase (PDE) isoenzymes of family IV (cAMP-specific family).
cAMP (adenosine cyclic 3xe2x80x2,5xe2x80x2-monophosphate) is a key second messenger, the concentration of which affects particular cell activities through activation of enzymes such as kinases. PDE IV is known to hydrolyse cAMP to its corresponding inactive 5xe2x80x2-monophosphate metabolite. Hence, inhibition of PDE IV leads to an elevation of cAMP levels in particular cells such as the respiratory smooth muscle cell and in a wide variety of inflammatory cells, i.e. certain lymphocytes, e.g. basophils, neutrophils and eosinophils, monocytes and mast-cells. A number of allergic, atopic and inflammatory diseases are deemed to be caused by higher-than-normal PDE IV concentrations which result in low cAMP levels and hypersensitivity of the thus affected cells for excitatory stimuli. (Examples of said hypersensitivity are for example, excessive histamine release from basophils and mast cells or excessive superoxide anion radical formation by eosinophils.) Hence, the present compounds having potent phosphodiesterase IV inhibitory properties are deemed useful agents in alleviating and/or curing allergic, atopic and inflammatory diseases. The functional effects of PDE IV inhibitors are e.g. respiratory smooth muscle relaxation, bronchodilation, platelet aggregation inhibition and inhibition of white blood cell mediator release. Examples of allergic diseases are bronchial asthma, cheilitis conjunctivitis, contact dermatitis and eczema, irritable bowel disease, deshydroform eczema, urticaria, vasculitis, vulvitis; examples of atopic diseases are dermatitis and eczema, winterfeet, asthma, allergic rhinitis; and related afflictions are, for example, psoriasis and other hyperproliferative diseases.
The present invention thus also relates to compounds of formula (I) as defined hereinabove for use as a medicine, in particular for use as an anti-asthmatic medicine or as a medicine for treating atopic diseases. Thus the compounds of the present invention may be used for the manufacture of a medicament for treating asthmatic or atopic diseases more; in particular atopic dermatitis.
The PDE IV inhibitory activity of the compounds of formula (I) may be demonstrated in the test xe2x80x9cInhibition of recombinant human mononuclear lymphocyte (MNL) phosphodiesterase type IV B produced in insect cells with a baculovirus vectorxe2x80x9d. Several in vivo and in vitro tests may be used to demonstrate the usefulness of the compounds of formula (I) in treating the described allergic, atopic and inflammatory diseases. Such tests are for instance, xe2x80x9cBronchoconstriction of the guinea pig trachea in vitroxe2x80x9d, xe2x80x9cBronchoconstriction of the guinea pig trachea in vivoxe2x80x9d and the in vivo test xe2x80x9cDextraninduced oedema formation in mouse earxe2x80x9d.
Further, the present compounds have only very low inhibitory activity on the phosphodiesterase isoenzymes of family III (cGMP-inhibited family). Inhibition of, in particular, PDE III leads to an elevation of cAMP in Ie cardiac muscle, thereby causing effects on the contractile force of the heart as well as on the relaxation of the heart. In the treatment of the described allergic, atopic and inflammatory diseases, cardiovascular effects clearly are undesired. Hence, as the present compounds inhibit PDE IV at much lower concentrations as they inhibit PDE III, their therapeutic use may be adjusted to avoid cardiovascular side-effects.
Art-known PDE IV inhibitors often cause adverse gastro-intestinal side effects. Most of the present compounds, however, have few effects on the gastro-intestinal tract, which may be demonstrated in the test xe2x80x9cGastric emptying of a caloric meal in ratsxe2x80x9d.
The designation PDE III and IV as used herein refers to the classification by J. A. Beavo and D. H. Reifsnyder, TIPS Reviews, April 1990, pp. 150-155.
The compounds of the present invention also have cytokine inhibitory activity. A cytokine is any secreted polypeptide that affects the function of other cells by modulating interactions between cells in the immune or inflammatory response. Examples of cytokines are monokines and lymphokines and they may be produced by a wide variety of cells. For instance, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte but many other cells produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes, and xcex2-lymphocytes. Lymphokines am generally referred to as being produced by lymphocyte cells. Examples of cytokines include Interleukin-1 (IL-1), Interleukin-2 (IL-2), Interleukin-6 (IL-6), Interleukin-8 (IL-8), alpha-Tumor Necrosis Factor (xcex1TNF) and beta-Tumor Necrosis Factor (xcex2TNF).
The cytokine specifically desired to be inhibited is xcex1TNF Excessive or unregulated TNF production is implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoartritis, gouty arthritis, and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft versus host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn""s disease, ulcerative colitis, or pyresis.
The cytokine inhibitory activity of the compounds of formula (I), such as the inhibition of xcex1TNF production, may be demonstrated in the in vitro test xe2x80x9cCytokine production in human whole blood culturesxe2x80x9d.
In addition, the compounds of the present invention are expected to show no or little endocrinological side-effects. This may be evidenced by, for instance, the xe2x80x9cTestosterone in vivoxe2x80x9d test the xe2x80x9cIn vitro inhibition of the aromatase activityxe2x80x9d-test and the xe2x80x9cIn vivo inhibition of the aromatase activityxe2x80x9d-test. In view of their useful PDE IV and cytokine inhibiting properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, topically, percutaneously, by inhalation or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gellies, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like. Application of said compositions may be by aerosol, e.g. with a propellant such as nitrogen, carbon dioxide, a freon, or without a propellant such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab. In particular, semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used.
In order to enhance the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions, it can be advantageous to employ xcex1-, xcex2- or xcex3-cyclodextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl- xcex2-cyclodextrin. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions. In the preparation of aqueous compositions, addition salts of the subject compounds are obviously more suitable due to their increased water solubility.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
In general it is contemplated that an effective daily amount would be from 0.01 mg/kg to 10 mg/kg body weight, more preferably from 0.04 mg/kg to 5 mg/kg body weight. It is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore guidelines only and are not intended to limit the scope or use of the invention to any extent.
The following examples are intended to illustrate and not to limit the scope of the present invention.
Experimental part
Compounds of formula (I) and some intermediates have a stereogenic center. In those cases where the racemate was separated into its enantiomers, the stereochemically isomeric form which was first isolated was designated as xe2x80x9cAxe2x80x9d and the second as xe2x80x9cBxe2x80x9d, without further reference to the actual stereochemical configuration. Hereinafter, xe2x80x9cDIPExe2x80x9d means diisopropylether, xe2x80x9cDMFxe2x80x9d means N,N-dimethylformamide and xe2x80x9cTHFxe2x80x9d means tetrahydrofuran.
A. Preparation of the intermediates